The present invention relates to xcex2-alanine derivative and a pharmaceutically acceptable salt thereof. More particularly, it relates to xcex2-alanine derivative and a salt thereof which is glycoprotein IIb/IIIa antagonist, inhibitor of blood platelets aggregation and inhibitor of the binding of fibrinogen to blood platelets.
In European Patent Application No. 512,831 A1, there are disclosed fibrinogen receptor antagonists.
In European Patent Application No. 445,796 A2, there are disclosed inhibitor of blood platelets aggregation.
The present invention relates to xcex2-alanine derivative and a salt thereof. More particularly, it relates to xcex2-alanine derivative and a salt thereof which is glycoprotein IIb/IIIa antagonist and inhibitor of platelet aggregation, and useful as:
a drug for the prevention and/or the treatment of diseases caused by thrombus formation such as arterial thrombosis; arterial sclerosis; ischemic heart diseases [e.g. angina pectoris (e.g. stable angina pectoris, unstable angina pectoris including imminent infarction, etc.), myocardial infarction (e.g. acute myocardial infarction, etc.), coronary thrombosis, etc.]; ischemic brain diseases [e.g. cerebral infarction {e.g. cerebral thrombosis (e.g. acute cerebral thrombosis, etc.), cerebral embolism, etc.}, transient cerebral ischemia (e.g. transient ischemic attack, etc.), cerebrovascular spasm after cerebral hemorrhage (e.g. cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc.]; pulmonary vascular diseases (e.g. pulmonary thrombosis, pulmonary embolism etc.); peripheral circulatory disorder [e.g. arteriosclerosis obliterans, thromboangiitis obliterans (i.e. Bxc3xcrger""s disease), Raynaud""s disease, complication of diabetes mellitus (e.g. diabetic angiopathy, diabetic neuropathy, etc.), phlebothrombosis (e.g. deep vein thrombosis, etc.), etc.] or the like;
a drug for the prevention and/or the treatment of restenosis and/or reocclusion such as restenosis and/or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis and/or reocclusion after the administration of thrombolytic drug (e.g. tissue plasminogen activator (TPA), etc.) or the like;
a drug for the adjuvant therapy with thrombolytic drug (e.g. TPA, etc.) or anticoagulant (e.g. heparin, etc.);
a drug for the prevention and/or the treatment of the thrombus formation in case of vascular surgery, valve replacement, extracorporeal circulation [e.g. surgery (e.g. open heart surgery, pump-oxygenator, etc.) hemodialysis, etc.], transplantation, or the like;
a drug for the prevention and/or the treatment of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, or the like;
a drug for inhibiting of metastasis; or the like.
The xcex2-alanine derivative of the present invention is expected to be useful as an inhibitor of cell adhesion and so is expected to be useful as
a drug for the prevention and/or the treatment of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g. nephritis, etc.), immune diseases, or the like;
a drug for inhibiting of metastasis; or the like.
Accordingly, one object of the present invention is to provide xcex2-alanine derivative or a salt thereof which is useful as stated above.
Another object of the present invention is to provide processes for preparation of said xcex2-alanine derivative or a salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said xcex2-alanine derivative or a salt thereof.
Still further object of this invention is to provide methods of using said xcex2-alanine derivative or a salt thereof for the prevention and/or the treatment of aforesaid diseases in a human being or an animal.
The object xcex2-alanine derivative of the present invention can be shown by the following formula (I): 
wherein
R1 is N-containing cycloalkyl which may have one or more suitable substituent(s),
R2 is carboxy or protected carboxy,
A1 is lower alkylene, lower alkanyl-ylidene or lower alkenylene, each of which may have one or more suitable substituent(s),
A2 is lower alkylene,
A3 is lower alkylene which may have one or more suitable substituent(s), 
xe2x80x83is a group of the formula: 
xe2x80x83(wherein 
xe2x80x83is N-containing heterocyclic group which may have one or more suitable substituent(s)),
X is O, S or NH,
Y is NH,
Z is 
xe2x80x83(wherein R3 is hydrogen or lower alkyl),
l, m and n are each the same or different an integer of 0 or 1,
or a pharmaceutically acceptable salt thereof.
The object compound (I) or a salt thereof can be prepared by the following processes. 
wherein
A4 is lower alkynylene,
Three R6 are independently lower alkyl,
R7 is lower alkyl,
Two R8 are independently halogen,
Three R9 are independently lower alkyl, and
R11 is lower alkyl.
Among the starting compounds (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), there are novel compounds. They can be prepared from the known compounds in a conventional manner in this field of the art or the similar manners to those disclosed in Preparations and/or Examples mentioned later in the present specification.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.] and the like.
In the above and subsequent descriptions of this specification, suitable examples of the various definitions are explained in detail as follows:
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
The term xe2x80x9chigherxe2x80x9d is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
The preferable number of the xe2x80x9cone or morexe2x80x9d in the term xe2x80x9cone or more suitable substituent(s)xe2x80x9d may be 1 to 4.
Suitable xe2x80x9clower alkylxe2x80x9d may be straight or branched ones such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl or the like.
Suitable xe2x80x9cprotected carboxyxe2x80x9d may be a conventional protecting group such as an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as
lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.] which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower-alkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.] or mono(or di or tri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.];
higher alkyl ester [e.g. heptyl ester, octyl ester, 3,5-dimethyloctyl ester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester, hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester, adamantyl ester, etc.];
lower alkenyl ester [e.g. (C2-C6)alkenyl ester,(e.g. vinyl ester, allyl ester, etc.)];
lower alkynyl ester [e.g. (C2-C6)alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.)];
ar(lower)alkyl ester which may have one or more suitable substituent(s) [e.g. phenyl(lower)alkyl ester which may have 1 to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl, or halo(lower)alkyl, (e.g. benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.)];
aryl ester which may have one or more suitable substituent(s) [e.g. phenyl ester which may have 1 to 4 lower alkyl, or halogen, (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.)];
cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)-[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or 2-)-[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or 2-)-[cycloheptyloxycarbonyloxy]ethyl ester, etc.), etc.];
(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or 2-)(5-methy-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; or the like,
in which the preferred one may be lower alkyl ester, lower alkanoyloxy(lower)alkyl ester, ar(lower)alkyl ester which may have one or more suitable substituent(s), cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl, higher alkyl ester, and [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl ester;
and the more preferred one may be methyl ester, ethyl ester, isobutyl ester, butyl ester, pentyl ester, hexyl ester, benzyl ester, 4-trifluoromethylbenzyl ester, 4-chlorobenzyl ester, adamantyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (1-cyclohexyloxycarbonyloxy)ethyl ester and pivaloyloxymethyl ester.
Suitable xe2x80x9clower alkanyl-ylidenexe2x80x9d may include straight or branched one such as methine, 1-ethanyl-2-ylidene, 1-propanyl-3-ylidene, 2-methyl-1-propanyl-3-ylidene, 7-pentanyl-5-ylidene, 1-hexanyl-6-ylidene and the like,
in which the preferred one may be (C1-C4)alkanyl-ylidene; and the more preferred one may be methine.
Suitable xe2x80x9clower alkylenexe2x80x9d may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 1-ethylethylene, 2-ethylpropylene, and the like, in which the preferred one may be (C1-C4)alkylene; and the more preferred one may be methylene, ethylene and trimethylene.
Suitable xe2x80x9clower alkenylenexe2x80x9d may include straight or branched one having 2 to 6 carbon atom(s) such as vinylene, propenylene, butenylene, 1 or 2 or 3-pentenylene, 1 or 2 or 3-hexenylene, methylvinylene, ethylvinylene, 1 or 2 or 3-methylpropenylene, 1 or 2 or 3-ethylpropenylene, 1 or 2 or 3 or 4-methyl-1 or 2-butenylene, or the like.
Suitable xe2x80x9camino protective groupxe2x80x9d may include acyl group as explained below, a conventional protecting group such as ar(lower)alkyl which may have 1 to 3 suitable substituent(s) (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc.), [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, etc.] or the like; and the like.
Suitable xe2x80x9cacyl groupxe2x80x9d and xe2x80x9cacylxe2x80x9d may include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like.
Suitable example of said xe2x80x9cacyl groupxe2x80x9d may be illustrated as follows.
Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
lower, or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.);
lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); or the like;
Aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e.g., phenyl(C1-C6)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(C1-C6)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc), etc.];
ar(lower)alkenoyl [e.g., phenyl(C3-C6)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(C3-C6)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.];
ar(lower)alkoxycarbonyl [e.g., phenyl(C1-C6)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);
arylcarbamoyl (e.g., phenylcarbamoyl, etc.);
arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);
arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);
arylsulfonyl which may have 1 to 4 lower alkyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like;
Heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.);
heterocyclicglyoxyloyl; or the like;
in which suitable xe2x80x9cheterocyclic moietyxe2x80x9d in the terms xe2x80x9cheterocycliccarbonylxe2x80x9d, xe2x80x9cheterocyclic(lower)alkylxe2x80x9d, heterocyclic(lower)alkenoylxe2x80x9d and xe2x80x9cheterocyclicglyoxyloylxe2x80x9d as mentioned above means, in more detail, saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl, quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.
The acyl moiety as mentioned above may have one to ten, same or different, suitable substituent(s) such as
lower alkyl (e.g., methyl, ethyl, propyl, etc.);
lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.);
lower alkylthio (e.g., methylthio, ethylthio, etc.);
lower alkylamino (e.g., methylamino, ethylamino, propylamino, etc.);
cyclo(lower)alkyl [e.g. cyclo(C3-C6)alkyl (e.g., cyclopentyl, cyclohexyl, etc.]);
cyclo(lower)alkenyl [e.g. cyclo(C3-C6)alkenyl (e.g., cyclohexenyl, cyclohexadienyl, etc);
halogen (e.g., fluorine, chlorine, bromine, iodine); amino; amino protective group as mentioned above; hydroxy; protected hydroxy as mentioned below; cyano; nitro; carboxy; protected carboxy as mentioned above; sulfo; sulfamoyl; imino; oxo;
amino(lower)alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy(lower)alkyl (e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc.), or the like.
Suitable xe2x80x9cprotected hydroxyxe2x80x9d may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
The more preferred example of xe2x80x9camino protective groupxe2x80x9d may be lower alkoxycarbonyl or ar(lower)alkoxycarbonyl and the most preferred one may be t-butoxycarbonyl or benzyloxycarbonyl.
Suitable xe2x80x9clower alkylenexe2x80x9d in the term xe2x80x9clower alkylene which may have one or more suitable substituent(s)xe2x80x9d can be referred to the ones as exemplified above.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d in the term xe2x80x9clower alkylene which may have one or more suitable substituent(s)xe2x80x9d may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.);
lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, etc.);
lower alkenyl [e.g. (C2-C6)alkenyl (e.g., vinyl,.1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.)];
lower alkynyl [e.g. (C2-C6)alkynyl (e.g., ethynyl, 1propynyl, propargyl, 1-methylpropargyl, 1-ethylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5 hexynyl, etc.);
mono(or di or tri)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, etc.);
halogen (e.g., chlorine, bromine, fluorine, iodine);
carboxy; protected carboxy as mentioned above; hydroxy;
protected hydroxy as mentioned above;
aryl (e.g., phenyl, naphthyl, etc.);
heterocyclic group as mentioned above [e.g. unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) (e.g. indolyl, isoindolyl, indolynyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl, quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.)];
ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.);
ar(lower)alkyl having one or more suitable substituent(s) such as ar(lower)alkyl having one or more (preferably 1 to 4) lower alkoxy, halogen, cyano, halo(lower)alkyl, lower alkylene dioxy or the like;
carboxy(lower)alkyl; protected carboxy(lower)alkyl; nitro; amino;
protected amino, i.e. amino protected by aforesaid xe2x80x9camino protective groupxe2x80x9d, preferably, acylamino, in which acyl moiety can be aforementioned xe2x80x9cacylxe2x80x9d, such as aliphatic acylamino such as lower or higher alkanoylamino (e.g., formylamino, acetylamino, propanoylamino, butanoylamino, 2-methylpropanoylamino, pentanoylamino, 2,2-dimethylpropanoylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino, undecanoylamino, dodecanoylamino, tridecanoylamino, tetradecanoylamino, pentadecanoylamino, hexadecanoylamino, heptadecanoylamino, octadecanoylamino, nonadecanoylamino, icosanoylamino, etc.), cyclo(lower)alkylcarbonylamino [e.g. cyclo(C3-C6)alkylcarbonylamino (e.g. cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, etc.)], lower or higher alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino, pentyloxycarbonylamino, heptyloxycarbonylamino, etc.), lower alkoxy(lower)alkanoylamino (e.g. methoxyacetylamino, 2- or 3-methoxypropionylamino, ethoxyacetylamino, 2- or 3-ethoxypropionylamino, etc.), lower alkynylcarbonylamino [e.g. (C2-C6)alkynylcarbonylamino (e.g. propargylcarbonylamino, 1-methylpropargylcarbonylamino, 1- or 2- or 3-butynylcarbonylamino, etc.), lower or higher alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, n-butylsulfonylamino, sec-butylsulfonylamino, t-butylsulfonylamino, n-pentylsulfonylamino, neo-pentylsulfonylamino, hexylsulfonylamino, etc.), lower or higher alkoxysulfonylamino (e.g., methoxy-sulfonylamino, ethoxysulfonylamino, etc.), aroylamino which may have one or more (preferably 1 to 3) suitable substituent(s) (e.g. benzoylamino, toluoylamino, naphthoylamino, 2- or 3- or 4-hydroxybenzoylamino, 2- or 3- or 4-methoxybenzoylamino, 2- or 3- or 4-chlorobenzoylamino, phenylbenzoylamino, etc.), ar(lower)alkanoylamino [e.g., phenyl(C1-C6)alkanoylamino (e.g., phenylacetylamino, phenylpropanoylamino, phenylbutanoylamino, phenylisobutanoylamino, phenylpentanoylamino, phenylhexanoylamino, etc.), naphthyl(lower)alkanoylamino (e.g., naphthylacetylamino, naphthylpropanoylamino, naphthylbutanoylamino, etc.), etc.], ar(lower)alkenoylamino [e.g., phenyl(C3-C6)alkenoylamino (e.g., phenylpropenoylamino, phenylbutenoylamino, phenylmethacryloylamino, phenylpentenoylamino, phenylhexenoylamino, etc.), naphthyl(C3-C6)alkenoylamino (e.g., naphthylpropenoylamino, naphthylbutenoylamino, etc.), etc.], ar(lower)alkoxycarbonylamino [e.g., phenyl(C1-C6)alkoxy-carbonylamino (e.g. benzyloxycarbonylamino, phenethyloxycarbonylamino, etc.), etc.], aryloxycarbonylamino (e.g., phenoxycarbonylamino, naphthyloxycarbonylamino, etc.), aryloxy(lower)alkanoylamino (e.g., phenoxyacetylamino, phenoxypropionylamino, etc.), arylcarbamoylamino (e.g., phenylcarbamoylamino, etc.), arylthiocarbamoylamino (e.g., phenylthiocarbamoylamino, etc.), arylglyoxyloylamino (e.g., phenylglyoxyloylamino, naphthylglyoxyloylamino, etc.), arylsulfonylamino (e.g. phenylsulfonylamino, p-tolylsulfonylamino, etc.), or the like;
di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.);
hydroxy(lower)alkyl; protected hydroxy(lower)alkyl; acyl as mentioned above; cyano; mercapto; oxo;
lower alkylthio(lower)alkyl (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, methylthioethyl, ethylthioethyl, etc.);
arylthio(lower)alkyl (e.g. phenylthiomethyl, phenylthioethyl, etc.);
arylsulfonyl(lower)alkyl (e.g. phenylsulfonylmethyl, phenylsulfonylethyl, p-tolylsulfonylmethyl, p-tolylsulfonylethyl, etc.);
lower alkylsulfonyl(lower)alkyl (e.g. methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, etc.);
acylamino(lower)alkyl, in which acyl moiety can be aforementioned xe2x80x9cacylxe2x80x9d [e.g., arylsulfonylamino(lower)alkyl (e.g., phenylsulfonylaminomethyl, phenylsulfonylaminoethyl, p-tolylsulfonylaminomethyl, p-tolylsulfonylethyl, etc.),
lower alkylsulfonylamino(lower)alkyl (e.g., methylsulfonylaminomethyl, ethylsulfonylaminomethyl, propylsulfonylaminomethyl, butylsulfonylaminomethyl, t-butylsulfonylaminomethyl, pentylsulfonylaminoethyl, etc.), etc.];
lower alkylcarbonyl(lower)alkyl (e.g. methylcarbonylmethyl, ethylcarbonylmethyl, propylcarbonylmethyl, etc.);
aroyl(lower)alkyl (e.g. benzoylmethyl, naphthoylmethyl, toluoylmethyl, anisoylmethyl, etc.);
heterocyclic(lower)alkyl such as (lower)alkyl having heterocyclic group as exemplified above [e.g. (C1-C6)alkyl having unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) (e.g. indolylethyl, isoindolylethyl, indolyinylmethyl, indolizinylethyl, benzimidazolylmethyl, quinolylethyl, dihydroquinolylmethyl, isoquinolylethyl, indazolylethyl, quinoxalinylethyl, dihydroquinoxalinylmethyl, benzotriazolylethyl, etc.)];
lower alkyl sulfamoyl(lower)alkyl (e.g. methylsulfamoylmethyl, ethylsulfamoylmethyl, n-propylsulfamoylmethyl, isopropylsulfamoylmethyl, n-butylsulfamoylmethyl, t-butylsulfamoylmethyl, methylsulfamoylethyl, etc.);
arylsulfamoyl(lower)alkyl (e.g. phenylsulfamoylmethyl, tolylsulfamoylmethyl, phenylsulfamoylethyl, naphthylsulfamoylmethyl, etc.);
lower alkylcarbamoyl(lower)alkyl (e.g. methylcarbamoylmethyl, ethylcarbamoylmethyl, n-propylcarbamoylmethyl, isopropylcarbamoylmethyl, n-butylcarbamoylmethyl, t-butylcarbamoylmethyl, methylcarbamoylethyl, etc.);
arylcarbamoyl(lower)alkyl (e.g. phenylcarbamoylmethyl, tolylcarbamoylmethyl, phenylcarbamoylethyl, naphthylcarbamoylmethyl, etc.); ar(lower)alkylcarbamoyl which may have one or more suitable substituent(s) (e.g. phenyl(C1-C6)alkylcarbamoyl which may have 1 to 3 lower alkoxy (e.g. 2-methoxyphenethylcarbamoyl, 3-methoxyphenethylcarbamoyl, 4-methoxyphenethylcarbamoyl, etc.) and the like,
in which the more preferred one may be (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; phenyl; phenyl(C1-C6)alkyl; phenyl(C1-C6)alkyl having 1 to 4 (C1-C6)alkoxy, halo(C1-C6)alkyl or (C1-C6)alkylene dioxy; (C1-C6)alkyl having unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s); cyano; amino; (C1-C6)alkanoylamino; aroylamino which may have 1 to 3 hydroxy, (C1-C6)alkoxy, halogen or phenyl; cyclo(C3-C6)alkylcarbonylamino; (C1-C6)alkoxy(C1-C6)alkylcarbonylamino; (C2C6)alkynylcarbonylamino; (C1-C6)alkylsulfonylamino; phenylsulfonylamino; phenyl(C1-C6)alkylcarbamoyl;
and the more preferred one may be methyl, ethyl, vinyl, ethynyl, cyano, phenyl, phenethyl, 2-methoxyphenethyl, 3-methoxyphenethyl, 4-methoxyphenethyl, 3,4-dimethoxyphenethyl, 3-trifluoromethylphenethyl, 3,4-methylenedioxyphenethyl, 2-indolylethyl, 4-methoxyphenethylcarbamoyl, phenylsulfonylamino, n-butylsulfonylaminomethyl, benzoylamino, amino, acetylamino, p-hydroxybenzoylamino, p-methoxybenzoylamino, p-chlorobenzoylamino, n-butanoylamino, cyclopropylcarbonylamino, 3-methoxypropionylamino, biphenylcarbonylamino and propargylcarbonylamino.
Suitable xe2x80x9cN-containing heterocyclic groupxe2x80x9d may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least nitrogen atom and which may also contain the other hetero-atom such as an oxygen, sulfur atom or the like.
And, especially preferable N-containing heterocyclic group may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, tetrahydroquinolyl (e.g. 1,2,3,4-tetrahydroquinolyl, etc.), dihydroquinolyl, isoquinolyl, indazolyl, quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiomorpholinyl, thiazolidinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like,
in which the preferred one may be saturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), or saturated 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s);
and the more preferred one may be piperidyl, pyrrolidinyl, morpholinyl and 1,2,3,4-tetrahydroquinolyl.
Suitable xe2x80x9cN-containing cyclo(lower)alkylxe2x80x9d in-the term xe2x80x9cN-containing cyclo(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d may include 3 to 8-membered cycloalkyl containing 1 to 3 nitrogen atom(s), for example, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, etc.
Suitable xe2x80x9csuitable substituent(s)xe2x80x9d in the term xe2x80x9cN-containing cyclo(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d may include oxo, amino protective group as mentioned above.
Suitable xe2x80x9csuitable substituent(s)xe2x80x9d in the term xe2x80x9clower alkylene, lower alkanyl-ylidene or lower alkenylene each of which may have one or more suitable substituent(s)xe2x80x9d, may include lower alkyl or oxo.
Suitable xe2x80x9csuitable substituent(s)xe2x80x9d in the term xe2x80x9cN-containing heterocyclic group which may have one or more suitable substituent(s)xe2x80x9d may include lower alkyl, phenyl, halogen or oxo.
Suitable xe2x80x9clower alkynylenexe2x80x9d may include the ones having 2 to 6 carbon atoms such as ethynylene, 2-propynylene, 2- or 3-butynylene, 2- or 3- or 4-pentynylene or 2- or 3- or 4- or 5-hexynylene.
In the compound (I) as explained above, the preferred one is the following compound (I-A):
Compound (I-A): 
wherein
R1 is 3 to 8 membered cycloalkyl containing 1 to 3 nitrogen atom(s) which may have one or more suitable substituent(s),
R2 is carboxy or esterified carboxy,
A1 is lower alkylene, lower alkanyl-ylidene or lower alkenylene, each of which may have one or more suitable substituent(s),
A2 is lower alkylene,
A3 is lower alkylene which may have one or more suitable substituent(s), 
xe2x80x83is a group of the formula:
wherein 
xe2x80x83is saturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have one or more suitable substituent(s), unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) which may have one or more suitable substituent(s) or saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) which may have one or more suitable substituent(s),
X is O, S, or NH,
Y is NH,
Z is 
xe2x80x83(wherein R3 is hydrogen or lower alkyl),
l is an integer of 0 or 1,
m is an integer of 0 or 1,
n is an integer of 0 or 1,
and the more preferred one is the aforementioned compound (I-A),
wherein
R1 is piperidyl which may have 1 or 2 oxo or [5(lower)alkyl-2-oxo-1,3-dioxol-4-yl]-(lower)alkyl, 
xe2x80x83is piperidyl, morpholinyl, tetrahydroquinolyl or pyrrolydinyl,
A3 is lower alkylene which may have 1 to 3 suitable substituent(s) selected from the group consisting of (C1-C6)alkyl;, (C2-C6)alkenyl; (C2-C6)alkynyl; phenyl; phenyl(C1-C6)alkyl; phenyl(C1-C6)alkyl having 1 to 4 (C1-C6)alkoxy, halo(C1-C6)alkyl or (C1-C6)alkylene dioxy; (C1-C6)alkyl having unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s); cyano; amino; (C1-C6)alkanoylamino; aroylamino which may have 1 to 3 hydroxy, (C1-C6)alkoxy, halogen or phenyl; cyclo(C3-C6)alkylcarbonylamino; (C1-C6)alkoxy(C1-C6)alkylcarbonylamino; (C2-C6)alkynylcarbonylamino; (C1-C6)alkylsulfonylamino; phenylsulfonylamino; and phenyl(C1-C6)alkylcarbamoyl;
R2, R3, A1, A2, X, Y or Z are each as defined above,
l is an integer of 0,
m is an integer of 0,
n is an integer of 0,
and the much more preferred one is the aforementioned compound (I-A),
wherein
R1 is piperidyl,
A1 is lower alkylene or lower alkanyl-ylidene,
A3 is lower alkylene which may have lower alkyl, lower alkynyl or lower alkanoylamino, 
xe2x80x83is piperidyl,
Z is 
R2, R3, A2, Y, l, m and n are each as defined in the more preferred one,
and the another much more preferred one is the aformentioned compound (I-A),
wherein
R1 is piperidyl,
A1 is lower alkylene or lower alkanyl-ylidene,
A3 is lower alkylene which may have lower alkyl, lower alkynyl or lower alkanoylamino, 
xe2x80x83is morpholinyl,
Z is 
R2, R3, A2, Y, l, m and n are each as defined in the more preferred one.
In the compound (I) as explained above, another preferred one is the following compound (I-B):
Compound (I-B): 
wherein
R1 is N-containing cycloalkyl which may have one or more suitable substituent(s),
R2 is carboxy or esterified carboxy,
A1 is lower alkylene, lower alkanyl-ylidene or lower alkenylene, each of which may have one or more suitable substituent(s),
A2 is lower alkylene,
A3 is lower alkylene which may have one or more suitable substituent(s), 
xe2x80x83is a group of the formula: 
wherein 
xe2x80x83is N-containing heterocyclic group which may Wave one or more suitable substituent(s),
X is O,
Y is NH,
Z is 
xe2x80x83(wherein R3 is hydrogen or lower alkyl),
l is an integer of 1,
m is an integer of 0 or 1,
n is an integer of 0 or 1,
and the more preferred one is the aforementioned compound (I-B),
wherein
R1 is piperidyl, piperazinyl or azetidinyl, each of which may have 1 or 2 oxo or [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl]-(lower)alkyl, 
xe2x80x83is piperidyl, morpholinyl, tetrahydroquinolyl or pyrrolydinyl,
A3 is lower alkylene which may have 1 to 3 suitable substituent(s) selected from the group consisting of (C1-C6)alkyl; (C2-C6)alkenyl; (C2-C6)alkynyl; phenyl; phenyl(C1-C6)alkyl; phenyl(C1-C6)alkyl having 1 to 4 (C1-C6)alkoxy, halo(C1-C6)alkyl or (C1-C6)alkylene dioxy;. (C1-C6)alkyl having unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s); cyano; amino; (C1-C6)alkanoylamino; aroylamino which may have 1 to 3 hydroxy, (C1-C6)alkoxy, halogen or phenyl; cyclo(C3-C6)alkanoylamino; (C1-C6)alkoxy(C1-C6)alkylcarbonylamino; (C2-C6)alkynylcarbonylamino; (C1-C6)alkysulfonylamino; phenylsulfonylamino; and phenyl(C1-C6)alkylcarbamoyl;
R2, R3, A1, A2, X, Y, Z or l are each as defined above,
m is an integer of 0,
n is an integer of 0,
and the much more preferred one is the aforementioned compound (I-B),
wherein
R1 is piperidyl,
A1 is lower alkylene,
A3 is lower alkylene which may have lower alkyl, lower alkynyl or lower alkanoylamino, 
xe2x80x83is piperidyl,
Z is 
R2, R3, A2, X, Y, l, m and n are each as defined in the more preferred one,
and the much more preferred one is the aforementioned compound (I-B),
wherein
R1 is piperidyl,
A1 is lower alkylene,
A3 is lower alkylene which may have lower alkyl, lower alkynyl or lower alkanoylamino, 
is morpholinyl,
Z is 
R2, R3, A2, X, Y, l, m and n are each as defined in the more preferred one.
In the compound (I) as explained above, another preferred one is the following compound (I-C):
Compound (I-C): 
wherein
R1 is piperidyl which may have 1 or 2 oxo or [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl]-(lower)alkyl,
R2 is carboxy or esterified carboxy,
A1 is lower alkanyl-ylidene or lower alkenylene,
A2 is lower alkylene,
A3 is lower alkylene which may have lower alkyl, lower alkynyl or lower alkanoylamino, 
xe2x80x83is a group of the formula:
wherein 
xe2x80x83is piperidyl, morpholinyl, tetrahydroquinolyl or pyrrolydinyl,
Y is NH,
Z is 
(wherein R3 is hydrogen),
l is 0,
m is an integer of 0 or 1,
n is an integer of 0 or 1,
and the other preferred one is the aforementioned compound (I-C),
wherein
A3 is lower alkylene having lower alkynyl or lower alkanoylamino, 
xe2x80x83is piperidyl or morpholinyl,
R1, R2, R3, A1, A2, X, Y, Z, and l are each as defined above,
m is an integer of 0,
n is an integer of 0,
The processes for preparing the object compound (I) of the present invention are explained in detail in the following.
Process 1
The object compound (Ia) or a salt thereof can be prepared by reacting a compound (II) or its reactive derivative at the carboxy group or a salt thereof with a compound (III) or its reactive derivative at the amino group or a salt thereof.
Suitable reactive derivative at the carboxy group of the compound (II) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl 
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivative can optionally be selected from them according to the kind of the compound (II) to be used.
Suitable salts of the compound (II) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
Suitable reactive derivative at the amino group of the compound (III) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.
Suitable salts of the compound (III) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound (II) in used in a free acid form or its salt form, the reaction is preferable carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide, N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkylphosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, methanesulfonyl chloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
Process 2
The object compound (Ib) or a salt thereof can be prepared by reacting a compound (IV) or its reactive derivative at the carboxy group or a salt thereof with a compound (V) or its reactive derivative at the amino group or a salt thereof.
This reaction can be carried out in a similar manner to that of Process 1 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. reactive derivative, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
Process 3
The object compound (IC) or a salt thereof can be prepared by reacting a compound (VII) or its reactive derivative at the carboxy group or a salt thereof with a compound (VI) or its reactive derivative at the amino group or a salt thereof.
This reaction can be carried out in a similar manner to that of Process 1 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. reactive derivative, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
Process 4
The object compound (Ie) or a salt thereof can be prepared by subjecting a compound (Id) or a salt thereof to elimination reaction of amino protective group.
This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium, sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The present invention includes within the scope of the invention the case that protected carboxy in R2 is transformed into carboxy.
Process 5
The object compound (Ig) or a salt thereof can be prepared by subjecting a compound (If) or a salt thereof to elimination reaction of the carboxy protective group.
This reaction can be carried out in a similar manner to that of Process 4 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 4.
Process 6
The object compound (Id) or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof to protecting reaction of amino.
This reaction can be carried out according to a conventional manner such as the one described in Examples or the similar manners thereto.
Process 7
The object compound (If) or a salt thereof can be prepared by subjecting the compound (Ig) or a alt thereof to protecting reaction of carboxy.
This reaction can be carried out according to a conventional manner such as the ones described in Examples or the similar manners thereto.
Process 8
The object compound (Ii) or a salt thereof can be prepared by subjecting a compound (Ih) or a salt thereof to elimination reaction of amino protective group.
This reaction can be carried out in a similar manner to that of Process 4 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. reactive derivative, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 4.
Process 9
The object compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ii) or its reactive derivative at the amino group, or a salt thereof to acylation reaction.
Suitable acylating agent to be used in the present acylation reaction may include the compound of the formula:
R10xe2x80x94OHxe2x80x83xe2x80x83(X)
(wherein R10 is acyl as mentioned before) or its reactive derivative, or a salt thereof.
Suitable reactive derivative at the amino group of the compound (Ii) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Ii) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Ii) with a silyl compound such as N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (Ii) with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative of the compound (X) may include an acid halide, an acid anhydride, an activated ester, and the like. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2+Nxe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); and the like. These reactive derivatives can optionally be selected from them accordingly to the kind of the compound (Ii) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
When the compound (Ii) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,N-carbonyl-bis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphate; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenylphosphite; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The processes for preparing the starting compounds (IV) and (V) are explained in detail in the following.
Process A
The object compound (IX) or a salt thereof can be prepared by reacting a compound (II) or its reactive derivative at the carboxy group or a salt thereof with a compound (VIII) or its reactive derivative at the amino group or a salt thereof.
This reaction can be carried out in a similar manner to that of Process 1 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. reactive derivative, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
Process B
The object compound (IV) or a salt thereof can be prepared by subjecting a compound (IX) or a salt thereof to elimination reaction of the carboxy protective group.
This reaction can be carried out in a similar manner to that of Process 4 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 4.
The present invention includes within the scope of the invention the case that amino protective group in R1 is transformed into amino.
Process C
The object compound (Va) or a salt thereof can be prepared by reacting a compound (6) with acid.
Compound (6) can be prepared as follows.
Compound (2) can be prepared by reacting a compound (1) with formalin, and both compound (4) and compound (5) can be prepared by reacting a compound (2) with a compound (3) to Lipase-catalyzed reaction, and compound (6) can be prepared by reacting compound (5) with aqueous ammonia.
The reaction of each step can be carried out in a conventional manner such as the ones described in Preparations.
Process D
The object compound (Vb) or a salt thereof can be prepared by reacting a compound (11) with acid.
Compound (11) can be prepared as follows.
Compound (9) can be prepared by reacting a compound (7) with a compound (8) (wittig reaction), and compound (11) can be prepared by reacting a compound (9) with a compound (10).
The reaction of each step can be carried out in a conventional manner such as the ones described in Preparations.
When the object compound (I) obtained by the above-mentioned processes is in a free form, it can be converted into a salt form in a conventional manner. On the other hand, when the object compound (I) thus obtained is in a salt form, it can be converted into a free form or another salt form also in a conventional manner.
The compounds obtained by the above Processes 1 to 9 and A to D can be isolated and purified by a conventional method such as pulverization, recrystallization, column-chromatography, reprecipitation of the like.
It is to be noted that each of the object compound (I) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
Now in order to show the utility of the object compound (I), some pharmacological test data of the representative compound (I) of the present invention are shown in the following.
Test 1: Effect on Platelet Aggregation Induced by Adenosine Diphosphate (ADP)
Test Compound
(1) the compound of Example 21 (3)
Test Method
Platelet rich plasma (PRP) which contains 3xc3x97108 platelets/ml was prepared from human blood. To the 225 xcexcl of PRP, 25 xcexcl of drug solution* was added, and then stirred for 2 minutes at 37xc2x0 C. To the solution 5 xcexcl of ADP (final 2.5 xcexcM) was added as an aggregation inducer. Aggregation was measured by using an aggregometer (NBS HEMA-TRACER 801). Activity of inhibitor (test compound) was expressed as IC100 value i.e. dose required for complete inhibition of platelet aggregation.
Drug solution* xe2x80x94 xe2x80x94 xe2x80x94 Test compound was dissolved in water.
The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
The object compound (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the diseases.
The pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention.
For applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation including aerosols from metered dose inhalator, nebulizer or dry powder inhalator.
While the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being or an animal, in case of oral administration, a daily dose of 0.001-200 mg of the object compound (I) per kg weight of a human being or an animal in generally given for the prevention and/or the treatment of aforesaid diseases in a human being or an animal.